Advertisement

Elucidating the beneficial effects of melphalan, adriamycin, and corticoids in combination with bortezomib against multiple myeloma in vitro

  • Julia Schäfer
  • Jürgen Burhenne
  • Johanna Weiss
  • Dirk TheileEmail author
Original Article
  • 35 Downloads

Abstract

Combining bortezomib with other anti-cancer drugs or glucocorticoids is more efficient in multiple myeloma than bortezomib alone. However, the molecular mechanism of this beneficial effect is largely unknown. To investigate the effects of these compounds on bortezomib’s anti-proliferative potency and its intracellular accumulation and potency to inhibit the chymotrypsin-like proteasomal subunit, seven myeloma cell lines were investigated after exposure to bortezomib alone or either combined with adriamycin plus dexamethasone (PAD regimen) or melphalan plus prednisolone (VMP regimen), respectively. PAD or VMP combinations did not alter cellular bortezomib uptake. However, PAD and VMP regimens increased bortezomib’s chymotrypsin-like subunit inhibitory potency. This likely originates from indirect proteasome modulation, because adriamycin, dexamethasone, melphalan, or prednisolone did not inhibit this subunit when used alone. Strikingly, the anti-proliferative potency of bortezomib was not enhanced but slightly lowered in some cell lines when used in combinations. Adriamycin, dexamethasone, melphalan, or prednisolone can enhance bortezomib’s chymotrypsin-like subunit inhibitory potency, likely by mechanisms indirectly influencing proteasome functionality.

Keywords

Bortezomib PAD VMP Multiple myeloma Proteasome inhibition 

Notes

Acknowledgements

The authors like to thank Magdalena Longo, Andrea Deschlmayr, and Stephanie Rosenzweig for their excellent technical support.

Author contribution statement

JS, JB, JW, and DT conceived and designed research. JS and DT conducted experiments. JB contributed analytical tools. JS, JW, and DT analyzed data. JS, JB, JW, and DT wrote the manuscript. All authors read and approved the manuscript.

Funding information

This study was financially funded by Deutsche Forschungsgemeinschaft (SFB/TRR79, subproject B10).

References

  1. André P, Cisternino S, Chiadmi F, Toledano A, Schlatter J, Fain O, Fontan JE (2005) Stability of bortezomib 1-mg/mL solution in plastic syringe and glass vial. Ann Pharmacother 39:1462–1466CrossRefGoogle Scholar
  2. Barlogie B, Mitchell A, van Rhee F, Epstein J, Morgan GJ, Crowley J (2014) Curing myeloma at last: defining criteria and providing the evidence. Blood 124:3043–3051CrossRefGoogle Scholar
  3. Barpe DR, Rosa DD, Froehlich PE (2010) Pharmacokinetic evaluation of doxorubicin plasma levels in normal and overweight patients with breast cancer and simulation of dose adjustment by different indexes of body mass. Eur J Pharm Sci 41:458–463CrossRefGoogle Scholar
  4. Bianchi G, Oliva L, Cascio P, Pengo N, Fontana F, Cerruti F, Orsi A, Pasqualetto E, Mezghrani A, Calbi V, Palladini G, Giuliani N, Anderson KC, Sitia R, Cenci S (2009) The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition. Blood 113:3040–3049CrossRefGoogle Scholar
  5. Clemens J, Longo M, Seckinger A, Hose D, Haefeli WE, Weiss J, Burhenne J (2014) Stability of the proteasome inhibitor bortezomib in cell based assays determined by ultra-high performance liquid chromatography coupled to tandem mass spectrometry. J Chromatogr A 1345:128–138CrossRefGoogle Scholar
  6. Clemens J, Seckinger A, Hose D, Theile D, Longo M, Haefeli WE, Burhenne J, Weiss J (2015) Cellular uptake kinetics of bortezomib in relation to efficacy in myeloma cells and the influence of drug transporters. Cancer Chemother Pharmacol 75:281–291CrossRefGoogle Scholar
  7. Collins GA, Goldberg AL (2017) The logic of the 26S proteasome. Cell 169:792–806CrossRefGoogle Scholar
  8. Czock D, Keller F, Rasche FM, Häussler U (2005) Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids. Clin Pharmacokinet 44:61–98CrossRefGoogle Scholar
  9. Dettmer S, Theile D, Schäfer J, Seckinger A, Burhenne J, Weiss J (2016) Proteasome inhibition correlates with intracellular bortezomib concentrations but not with antiproliferative effects after bolus treatment in myeloma cell lines. Naunyn Schmiedeberg’s Arch Pharmacol 389:1091–1101CrossRefGoogle Scholar
  10. Ema.europa.eu [Internet]. London (UK): assesment report Neofordex [cited: 2018 May 18th]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessment_report/human/002418/WC500177562.pdf
  11. Fonseca R, Abouzaid S, Bonafede M, Cai Q, Parikh K, Cosler L, Richardson P (2017) Trends in overall survival and costs of multiple myeloma, 2000-2014. Leukemia 31:1915–1921CrossRefGoogle Scholar
  12. Frankfurt O, Rosen ST (2004) Mechanisms of glucocorticoid-induced apoptosis in hematologic malignancies: updates. Curr Opin Oncol 16:553–563CrossRefGoogle Scholar
  13. Gandolfi S, Laubach JP, Hideshima T, Chauhan D, Anderson KC, Richardson PG (2017) The proteasome and proteasome inhibitors in multiple myeloma. Cancer Metastasis Rev 36:561–584CrossRefGoogle Scholar
  14. Herr I, Gassler N, Friess H, Büchler MW (2007) Regulation of differential pro- and anti-apoptotic signaling by glucocorticoids. Apoptosis 12:271–291CrossRefGoogle Scholar
  15. Mai EK, Bertsch U, Dürig J, Kunz C, Haenel M, Blau IW, Munder M, Jauch A, Schurich B, Hielscher T, Merz M, Huegle-Doerr B, Seckinger A, Hose D, Hillengass J, Raab MS, Neben K, Lindemann HW, Zeis M, Gerecke C, Schmidt-Wolf IG, Weisel K, Scheid C, Salwender H, Goldschmidt H (2015) Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma. Leukemia 29:1721–1729CrossRefGoogle Scholar
  16. Mateos MV, Oriol A, Martínez-López J, Gutiérrez N, Teruel AI, de Paz R, García-Laraña J, Bengoechea E, Martín A, Mediavilla JD, Palomera L, de Arriba F, González Y, Hernández JM, Sureda A, Bello JL, Bargay J, Peñalver FJ, Ribera JM, Martín-Mateos ML, García-Sanz R, Cibeira MT, Ramos ML, Vidriales MB, Paiva B, Montalbán MA, Lahuerta JJ, Bladé J, Miguel JF (2010) Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol 11:934–941CrossRefGoogle Scholar
  17. Mateos MV, Oriol A, Martínez-López J, Teruel AI, Bengoechea E, Palomera L, de Arriba F, Esseltine DL, Cakana A, Pei L, van de Velde H, Miguel JS (2016) Outcomes with two different schedules of bortezomib, melphalan, and prednisone (VMP) for previously untreated multiple myeloma: matched pair analysis using long-term follow-up data from the phase 3 VISTA and PETHEMA/GEM05 trials. Ann Hematol 95:2033–2041CrossRefGoogle Scholar
  18. Mitsiades N, Mitsiades CS, Richardson PG, Poulaki V, Tai YT, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Schlossman R, Munshi NC, Hideshima T, Anderson KC (2003) The proteasome inhibitor PS-341 potentiates sensitivity of multiple myeloma cells to conventional chemotherapeutic agents: therapeutic applications. Blood 101:2377–2380CrossRefGoogle Scholar
  19. Pitcher DS, de Mattos-Shipley K, Tzortzis K, Auner HW, Karadimitris A, Kleijnen MF (2015) Bortezomib amplifies effect on intracellular proteasomes by changing proteasome structure. EBioMedicine 2:642–648CrossRefGoogle Scholar
  20. Roelofs J (2015) Proteasome inhibition by bortezomib: a left hook and a right punch. EBioMedicine 2:619–620CrossRefGoogle Scholar
  21. Shabaneh TB, Downey SL, Goddard AL, Screen M, Lucas MM, Eastman A, Kisselev AF (2013) Molecular basis of differential sensitivity of myeloma cells to clinically relevant bolus treatment with bortezomib. PLoS One 8:e56132CrossRefGoogle Scholar
  22. Sonneveld P, Schmidt-Wolf IGH, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM (2012) Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol 30:2946–2955CrossRefGoogle Scholar
  23. Sonneveld P, Goldschmidt H, Rosinol L, Bladé J, Lahuerta JJ, Cavo M, Tacchetti P, Zamagni E, Attal M, Lokhorst HM, Desai A, Cakana A, Liu K, van de Velde H, Esseltine DL, Moreau P (2013) Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials. J Clin Oncol 31:3279–3287CrossRefGoogle Scholar
  24. Sviland L, Leggat H, Harris AL, Bird G, Proctor SJ (1987) Short course intermediate dose intravenous melphalan therapy in myeloma--relation to early emergence of drug resistance (phase II study). Acta Haematol 78:233–238CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Clinical Pharmacology and PharmacoepidemiologyHeidelberg University HospitalHeidelbergGermany

Personalised recommendations